To develop effective therapeutic and vaccine strategies to combat infections with HIV-1, the cause of AIDS, it is essential to understand the cell-mediated immune response to this infectious agent. Towards this end, model systems for immunization with HIV proteins are being devised and used to test the ability of these proteins to stimulate various subsets of T lymphocytes. Initial experiments have utilized a mouse model. Animals were immunized with recombinant vaccinia virus containing an expressible form of the env gene of the IIIb strain of HIV-1, encoding the gp160 molecule. Lymphoid cells from such immunized mice were restimulated in vitro either with vaccinia recombinant virus infected cells or transfected cells expressing the gp160 protein. H-2 alpha T cells from such restimulated cultures were found to contain cytotoxic T lymphocytes (CTL) with specificity for the gp160 protein in the context of H-2Dd. No such responses were observed with cells from H-2k mice. Synthetic peptides corresponding to segments of the gp160 molecule were used to map the sites being recognized by these CTL. Only a single major recognition site was identified that appeared to be the target of essentially all CTL elicited under these conditions. This site was in an area of extensive sequence variation among isolates of HIV-1. These data indicate that there may be significant effects of MHC gene polymorphism on the response to HIV proteins and that the immunodominant regions may be subject to strong selection in vivo, resulting in viral escape from immune recognition following immunization with antigen corresponding to a single sequence. Additional studies are underway to extend these observations to other HIV proteins and to responses by human T cells.